A PRECLINICAL MODEL OF ALCOHOLIC HEPATITIS

酒精性肝炎的临床前模型

• 批准号: 10213324
• 负责人: ARUN J SANYAL
• 金额: $ 37.65万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-25 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213324
• 关键词: Acceleration; Alcohol Phenotype; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholic Hepatitis; Alcoholic steatohepatitis; Alcohols; Animal Model; Bilirubin; Chronic; Data; Development; Diet; Disease; Disease Progression; Disease regression; Dose; Epigenetic Process; Fibrosis; Funding Mechanisms; Generations; Genes; Genetic Drift; Goals; High Fat Diet; Histology; Human; Inbreeding; Individual; Insulin Resistance; Knowledge; Liver; Malnutrition; Modeling; Morbidity - disease rate; Mouse Strains; Mus; Mutation; National Institute on Alcohol Abuse and Alcoholism; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Parents; Pathway interactions; Patients; Pattern; Phase; Pre-Clinical Model; Predisposition; Process; Protocols documentation; Public Health; Reagent; Research Personnel; Role; Safety; Sampling; Severities; Signal Pathway; Signal Transduction; Site; Steatohepatitis; Supervision; Testing; Therapeutic; Thinness; Translating; Validation; alcohol effect; alcohol exposure; base; clinically significant; dietary manipulation; drug testing; druggable target; feeding; high reward; high risk; human data; insight; liver function; liver injury; metabolome; microbiome; microbiome analysis; mortality; mouse model; mutant; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; obesogenic; offspring; prevent; response; therapeutic development; therapeutic target; transcriptome

Alcoholic Steatohepatitis (ASH) is a major cause of liver related mortality. Despite its public health significance, there has been limited therapeutic advances for ASH. A principal barrier to acceleration of therapeutics is the availability of a robust preclinical model of ASH which recapitulates human ASH. Such models are needed to better understand the role of specific genes and pathways in human ASH e.g. the PNPLA3 mutation which is associated with severe ASH and test promising compounds for both efficacy and safety. In this UH2/UH3 application, we propose to provide “proof of concept” that our recently validated diet-induced animal model of NAFLD (DIAMOND) can be leveraged as a model of ASH with specific alcohol feeding protocols and will test the following novel hypothesis: an inbred isogenic crossed C57Bl/6J and 129S1/SvlmJ (B6/S129) mouse strain will develop steatohepatitis that recapitulates the key features of human ASH with alcohol feeding. Furthermore, liver-specific expression of the human mutant I148M PNPLA3 in this mouse will accelerate the development of ASH upon alcohol feeding. As per RFA AA-18-006, the studies will be performed in two phases: UH2 Phase (yrs. 01-02): To demonstrate that alcohol feeding causes steatohepatitis resembling human ASH with respect to histology, markers of liver injury and function, and activation of signaling pathways in an isogenic strain of B6/S129 mice. Alcohol feeding will be done along with chow- or an obesogenic-diet. We will test the effect of the NIAAA alcohol model feeding strategy (to be performed at NIAAA under supervision by Dr. Gao) and an alternate strategy where we will perform single ascending dose (SAD) and multiple ascending dose (MAD) studies that will provide optimized alcohol feeding strategies including amounts given chronically along with binges to allow a phenotype of ASH to develop. We will also test the ability to accelerate development of ASH by liver-specific expression of the human I148M PNPLA3 mutant gene. These data are based on preliminary data indicating that NASH can be accelerated by this maneuver. A minimal requirement for development of ASH (steatohepatitis, increased AST and bilirubin) will be needed to proceed to the UH3 phase. UH3 Phase (yrs. 03-05): To further validate the model, define the course of disease progression and regression by modulation of alcohol intake, and the impact of ASH on the susceptibility to ASH in subsequent generations. The transcriptome, metabolome and microbiome of the model will be related to human data from the AlcHepNet consortium. Also, the effects of alcohol withdrawal after varying durations of exposure will be tested to define the “off-response”. We will also perform studies to determine the susceptibility of offspring of mice that have been allowed to develop ASH and then recover by withdrawing alcohol. Microbiome analyses will be done at the UCSD site of AlcHepNet. The investigators have the required expertise in ASH and mouse models of NASH and ASH. Together the studies will have a high impact by providing a mouse model of ASH. The project also meets the high-risk high reward criteria for the UH2/UH3 funding mechanism.

酒精性脂肪性肝炎（ASH）是肝相关死亡率的主要原因。尽管公共健康的意义 灰烬的治疗进展有限。加速疗法的主要障碍是 可用的灰分临床前模型，该模型概括了人灰。需要这样的模型 更好地了解特定基因和途径在人灰中的作用，例如PNPLA3突变是 与效率和安全性的严重灰分和测试化合物相关。在此UH2/UH3中 应用，我们建议提供“概念证明”，以表明我们最近经过验证的饮食诱导的动物模型 NAFLD（钻石）可以用作特定酒精喂养方案的灰分模型，并将测试 以下新的假设：一种近交的近交性交叉C57BL/6J和129S1/SVLMJ（B6/S129）小鼠菌株 将发展出脂肪性肝炎，从而概括了通过饮酒的人灰的关键特征。此外， 该小鼠中人类突变体I148M PNPLA3的肝特异性表达将加速 灰烬喂食。根据RFA AA-18-006，研究将分为两个阶段：UH2期 （Yrs。01-02）：证明酒精喂养会导致类似于人灰的脂肪性肝炎 对于组织学，肝损伤和功能的标志物，以及在等源性应变中的信号通路的激活 B6/S129小鼠。酒精喂养将与Chow-或肥胖饮食一起进行。我们将测试 NIAAA酒精模型喂养策略（在Gao博士的监督下在NIAAA进行）和 我们将执行单次上升剂量（SAD）和多个上升剂量（疯狂）的替代策略 将提供优化的酒精喂养策略的研究，包括长期给予的金额 binges允许灰烬表型发育。我们还将测试加速灰分发展的能力 通过人I148M PNPLA3突变基因的肝特异性表达。这些数据基于初步数据 表明纳什可以通过这种操作加速。灰分开发的最低要求 （脂肪性肝炎，AST和胆红素增加）将需要进入UH3阶段。 UH3阶段（YRS。 03-05）：为了进一步验证模型，通过调节来定义疾病进展和回归的进程 酒精摄入量以及灰分对随后几代人敏感性的影响。 模型的转录组，代谢组和微生物组将与炼金术的人类数据有关 财团。此外，将测试不同暴露持续时间后戒酒的影响以定义 “反响应”。我们还将进行研究，以确定具有 被允许发育灰分，然后通过提取酒精来恢复。微生物组分析将在 Alchepnet的UCSD站点。研究人员在纳什的灰分和鼠标模型中具有所需的专业知识 和灰。通过提供灰分的小鼠模型，研究将产生很大的影响。该项目也是如此 符合UH2/UH3资金机制的高风险高奖励标准。